rs4561

Variant names:

• chr5-95816609-A-G
• rs4561
• NM_001118890.2:c.225T>C

Your query was ambiguous. Multiple possible variants found:

• chr5-95816609-A-G
• chr5-95816609-A-T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_001118890.2(GLRX):​c.225T>C​(p.Ile75Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.393 in 1,580,096 control chromosomes in the GnomAD database, including 125,296 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.37 (10776 hom., cov: 31)
  • Exomes 𝑓: 0.40 (114520 hom.)
• Consequence: GLRX NM_001118890.2 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.15
• Publications: 35 publications found

Genes affected

GLRX (HGNC:4330): (glutaredoxin) This gene encodes a member of the glutaredoxin family. The encoded protein is a cytoplasmic enzyme catalyzing the reversible reduction of glutathione-protein mixed disulfides. This enzyme highly contributes to the antioxidant defense system. It is crucial for several signalling pathways by controlling the S-glutathionylation status of signalling mediators. It is involved in beta-amyloid toxicity and Alzheimer's disease. Multiple alternatively spliced transcript variants encoding the same protein have been identified. [provided by RefSeq, Aug 2011]

RHOBTB3 (HGNC:18757): (Rho related BTB domain containing 3) Enables ATP binding activity and small GTPase binding activity. Involved in retrograde transport, endosome to Golgi. Located in extracellular exosome. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP7: Synonymous conserved (PhyloP=-1.14 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.417 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLRX	NM_001118890.2	c.225T>C	p.Ile75Ile	synonymous_variant	Exon 2 of 3	ENST00000237858.11	NP_001112362.1
GLRX	NM_001243658.2	c.225T>C	p.Ile75Ile	synonymous_variant	Exon 2 of 3		NP_001230587.1
GLRX	NM_001243659.2	c.225T>C	p.Ile75Ile	synonymous_variant	Exon 2 of 3		NP_001230588.1
GLRX	NM_002064.3	c.225T>C	p.Ile75Ile	synonymous_variant	Exon 2 of 3		NP_002055.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLRX	ENST00000237858.11	c.225T>C	p.Ile75Ile	synonymous_variant	Exon 2 of 3	1	NM_001118890.2	ENSP00000237858.6

Frequencies

GnomAD3 genomes AF: 0.371 AC: 56350 AN: 151844 Hom.: 10779 Cov.: 31

Gnomad AFR AF: 0.329

Gnomad AMI AF: 0.422

Gnomad AMR AF: 0.310

Gnomad ASJ AF: 0.419

Gnomad EAS AF: 0.178

Gnomad SAS AF: 0.367

Gnomad FIN AF: 0.374

Gnomad MID AF: 0.424

Gnomad NFE AF: 0.421

Gnomad OTH AF: 0.393

GnomAD2 exomes AF: 0.363 AC: 91306 AN: 251296 AF XY: 0.373

Gnomad AFR exome AF: 0.324

Gnomad AMR exome AF: 0.222

Gnomad ASJ exome AF: 0.415

Gnomad EAS exome AF: 0.181

Gnomad FIN exome AF: 0.384

Gnomad NFE exome AF: 0.425

Gnomad OTH exome AF: 0.388

GnomAD4 exome AF: 0.395 AC: 564812 AN: 1428134 Hom.: 114520 Cov.: 26 AF XY: 0.397 AC XY: 282892 AN XY: 712506

African (AFR) AF: 0.313 AC: 10289 AN: 32878

American (AMR) AF: 0.232 AC: 10362 AN: 44680

Ashkenazi Jewish (ASJ) AF: 0.412 AC: 10701 AN: 25954

East Asian (EAS) AF: 0.162 AC: 6414 AN: 39566

South Asian (SAS) AF: 0.387 AC: 33129 AN: 85634

European-Finnish (FIN) AF: 0.386 AC: 20619 AN: 53382

Middle Eastern (MID) AF: 0.475 AC: 2702 AN: 5692

European-Non Finnish (NFE) AF: 0.414 AC: 447668 AN: 1081106

Other (OTH) AF: 0.387 AC: 22928 AN: 59242

GnomAD4 genome AF: 0.371 AC: 56369 AN: 151962 Hom.: 10776 Cov.: 31 AF XY: 0.367 AC XY: 27291 AN XY: 74266

African (AFR) AF: 0.329 AC: 13611 AN: 41422

American (AMR) AF: 0.310 AC: 4735 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.419 AC: 1453 AN: 3466

East Asian (EAS) AF: 0.179 AC: 928 AN: 5188

South Asian (SAS) AF: 0.368 AC: 1767 AN: 4800

European-Finnish (FIN) AF: 0.374 AC: 3945 AN: 10542

Middle Eastern (MID) AF: 0.429 AC: 126 AN: 294

European-Non Finnish (NFE) AF: 0.421 AC: 28598 AN: 67960

Other (OTH) AF: 0.392 AC: 823 AN: 2102

Alfa AF: 0.405 Hom.: 27382

Bravo AF: 0.363

Asia WGS AF: 0.264 AC: 919 AN: 3478

EpiCase AF: 0.433

EpiControl AF: 0.431

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.096
DANN	Benign	0.49
PhyloP100		-1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs4561; hg19: chr5-95152313; COSMIC: COSV52986908;